MURAMATSU, INUKAI, AND UEDA
2546
VOL.30
The Radiation-Induced Addition Reaction of Alcohols to 1,Z-Dichlorotetrafluorocyclobutene and 1,Z-Dichlorohexafluorocyclopentene HIROSHIGE MURAMATSU, KANINUKAI, AND TERUO UEDA Government Industrial Research Institute, Nagoya, Kita-ku, Nagoya, J a p a n Received February 26, 1966 Various alcohols containing polyfluorocycloalkyl or polyfluorocycloalkenyl groups have been synthesized by the addition reaction of alcohols, such as methanol, ethanol, and 1- and 2-propanol, to l12-dichlorotetrafluorocyclobutene and 1,2-dichlorohexafluorocyclopenteneunder y-ray irradiation. While only the polyfluorocyclopentenylcarbinols were obtained in the addition to the halocyclopentene, the addition of alcohols to the halocyclobutene gave both the 1:1 adduct and the dehydrochlorinated 1: 1 adduct, whose molar ratio varied markedly with the structure of the alcohols.
Reports on the synthesis of the alcohols containing polyfluorocycloalkyl or polyfluorocycloalkenyl groups have been meager. Barrick and co-workers’ synthesized (2,2,3,3-tetrafluoroc y clobut yl) carbinol and (3,3 ,4,4-tetrafluoro-l-cyclobutenyl)isopropylcarbinolby the cycloaddition reactions of tetrafluoroethylene with allyl alcohol and ethynylisopropylcarbinol, respectively. Several substituted perfluorocyclobutanols2 were prepared by the reaction of perfluorocyclobutanone and a variety of unsaturated compounds such as propylene, methylacetylene, and allene. Polyfluorocyclobutenyldimethyl carbinol^^ were recently obtained in the reaction of tetrafluoroethylene or trifluorochloroethylene with 3-methyl-1-butyn-3-01. In a previous r e p ~ r tthe , ~ addition reaction of alcohols t o various chlorofluoroethylenes under y-ray irradiation was reported to take place to give the 1: 1 adducts in appreciable yields. The addition reactions of alcohols, such as methanol, ethanol, and 1- and 2-propanol, have been further extended to 1,2-dichlorotetrafluorocyclobutene and 1,2-dichlorohexafluorocyclopenteneto obtain the polyfluorocycloalkyl- and polyfluorocycloalkenylcarbinols. These carbinols are potential intermediates for the synthesis of versatile derivatives of polyfluorocycloalkanes and polyfluorocycloalkenes. Mixtures of the halocyclobutene or halocyclopentene and an alcohol in a molar ratio of 1:3 were irradiated in a glass tube at a rate of 0.59 X lo5 r./hr. for a period of about 3 weeks a t room temperature. The products from the addition of alcohols to 1,2-dichlorotetrafluorocyclobutene were found to be a mixture of the 1: 1 adduct I and the dehydrochlorinated 1: 1 adduct I1 as shown in thee quation. The molar ratios of I to I1 RR’CHOH
f
“’n:
varied markedly with the structure of the alcohols. The results are shown in Table I with the yields. TABLE I ADDITIONOF ALCOHOLS TO
Expt.
no.
(1
1,2-DICHLOROTETRAFLUOROCYCLOBUTENE Total yield of Total 1 : 1 ad- Composition of 1:1 ducts,“ -adducts, %dosage X 106,r. % I I1 Alcohols
1 CHaOH 2 CzHsOH 3 CzHsOH 4 n-C3H70H 5 n-CaH7OH 6 i-CaH70H 7 i-CaH70H Based on the amount of
33 21 57 43 30 61 74 26 71 75 25 31 19 54 46 22 23 52 48 29 49 7 93 22 38 64 7 93 the halocyclobutenes added.
From these results, it seems that two factors, ease of the hydrogen abstraction from the alcohols and steric interference of alkyl groups of the alcohols, effect the ratio of I to 11. The ratio is almost independent of the total dosage applied. The dehydrochlorinated 1: 1 adducts are thought to be formed by a mechanism similar to that proposed for the addition reaction of ethers6 to halocyclobutenes and halocyclopentenes.
+ H.
RR~OH
RR’CHOH
RR’COH
RR’COH
’I-ray_
c1
RR’COH
RR’COH Cl
C1
I11 Cl
Cl
I
I1
cis and trans
R
=
H or C H 3 ; R’
=
H , CH3, or C2H5
(1) D. D. Coffman, P. L. Barrick, R. D. Cramer, and M. S. Raasch, 490 (1949); P. L. Barrick, U. S. Patent 2,462,345
J. Am. Chem. Soc., 71,
(1949). (2) D. C. England, J. Am. Chem. Soc., 88, 2205 (1961). (3) J. D. Park and W. C. Frank, J. Ow. Chem., 29, 1445 (1964). (4) H. Muramatsu, ibid., 27, 2325 (1962).
n=2or3
The radical dechlorination of I11 would compete with the abstraction of a hydrogen from the alcohol to give the 1: 1 adduct I. Therefore, the more reactive alcohol, whose a-hydroxyalkyl radical formed by the hydrogen abstraction was stabilized by resonance, would be expected to give predominantly I. It was found in the radical addition of ethers4 that the ratio of the 1 : l adduct to the dehydrochlorinated 1: 1 adduct increased (5) H. Muramatau and K. Inukai, ibid., SO, 544 (1985).
AUGUST1965
RADIATION-INDUCED ADDITIONS OF ALCOHOLS TO CYCLO OLEFINS
with the apparent reactivity of the ethers. The difference of the molar ratio of I to I1 between methanol and ethanol may be explained by the above reasoning. The increase of the ratio from the case of ethanol to that of 2-propanol, however, would be due to the steric effect of the alkyl groups in the alcohols. The gas chromatogram of the 1: 1 adducts I exhibited the presence of cis and trans forms in the halocyclobutyl group. Some of these isomers were separated using a preparative gas chromatograph. Both isomers gave the same 2-chlorotetrafluorocyclobutenylalkylcarbinol on treatment by alcoholic potassium hydroxide. The ratios of the both stereoisomers were calculated from the area of their peaks and the result is shown in Table 11, The isomer A has a slightly lower boiling point and a smaller retention time compared with the isomer B. When R and R’ in I were bulky groups, the steric interference with the neighboring groups was shown by molecular models to be larger in the isomer where the chlorine atoms are trans. From the results of Table 11,therefore, the isomer A would be the trans form and the isomer B the cis form. TABLE I1 COMPOSITION OF STEREOISOMERS IN THE 1 :1 ADDUCTS RR’COH
;
cl@ H c1 Expt. no.
1 2 3 4 5 6 7
: 1 adducts-
1-
c
R
R’
H H H H H CHI CHI
H CHI CH3 CzH5 C2H5 CHI CH3
-
Isomer B,
Isomer A,
%
%
51 33 36 32 36
49 67 64 68 64 93 95
7 5
The addition of the alcohols to 1,Bdichlorohexafluorocyclopentene gave almost exclusively the corresponding dehydrochlorinated 1: 1 adducts IV as occurred in the additions of ether^.^ I n the addition RR’COH
RR’CHOH
4-
“’DFk b”;. +
C1
F2
C1
F2
IV R=HorCH3;R’=H,CH3,0rC2Hs
of methanol, a small amount of a compound, white needle crystals of m.p. 103O, was obtained along with the chlorohexafluorocyclopentenylcarbinol, and its structure was tentatively assigned as V from elemental analysis and the infrared spectrum. The physical
v properties and results of analyses of the 1:l adducts and the dehydrochlorinated 1 : l adducts are listed in Tables 111, IV, and V.
2547
The dechlorination of methyl- and ethyl (1,2-dichlorotetrafluorocyclobuty1)carbinols with zinc dust gave the corresponding alkyl (tetrafluoro-1-cyclobuteny1)carbinols. The methyl (tetrafluoro-1-cyclobutenyl) carbinol thus obtained was dehydrated with phosphoric anhydride to yield 3,3,4,4-tetrafluoro-1-cyclobutenylethylene which is known to be synthesized by the cycloaddition of tetrafluoroethylene and ethynylethylene.’ The physical properties of the alkyl (tetrafluoro-lcyclobuteny1)carbinols are shown in Table VI. RCHOH
RCHOH
H
C1
R = CH3 or CZHS CH3C HOH
CH=CHa
Experimental* Addition Reactions of Alcohols to 1,2-Dichlorotetrafluorocyc1obutene.-A mixture of 95 g. (0.49 mole) of 1,2-dichlorotetrafluorocyclobutene and 81 g. (1.76 moles) of ethanol was added to a glass tube, 20 X 5 cm. (ca. 300-ml. capacity). The reaction tube was then sealed and received ?-irradiation a t room temperature to a total dosage 3.1 X 107 r. for a period of 564 hr. Distillation of the irradiation products, after the removal of the unchanged olefin (21 g.) and ethanol, gave 18 g. (0.087 mole, 18% yield) of methyl(2-chloro-3,3,4,4tetrafluoro-1-cyclobutenyl)carbinol, b.p. 96-98’ (48 mm.), 63 g. (0.26 mole, 53% yield) of methyl(l,2-dichloro-3,3,4,4tetrafluorocyclobutyl)carbinol, b.p. 103-106° (48 mm.), and ca. 3 g. of a viscous residue. The infrared spectrum of the methylhalocyclobutenylcarbinol exhibited a free OH band at 2.79 p (sh), a broad hydrogen-bonded OH band at 2.98 p, and a C=C band a t 6.06 M . The gas chromatogram7 of methyl(dichlorotetrafluorobuty1)carbinol obtained showed two peaks with retention times of 4.9 and 5.8 min., indicating the existence of the two stereoisomers. Both the stereoisomers were separated using preparative gas chromatography and were treated with alcoholic potassium hydroxide to give the same methyl(2-chlorotetrafluoro-l-cyclobutenyl)carbinol. The isomer with the retention time of 4.9 min. melted a t 41-45’ and had infrared absorption bands a t 2.86 (m), 3.34 (w), 3.38 (w), 7.05 (m), 7.31 (vs), 7.70 (m). 7.80 (m), 7.88 (m), 8.06 (m), 8.44 (s), 8.62 (s), 8.96 (m), 9.32 (m), 9.59 (m), 10.33 (w), 10.76 (m), 11.17 (m), 11.96 (vs), 13.19 (m), and 14.75 (w) p . The other isomer with the retention time of 5.8 min. melted a t 48-49” and had infrared absorption bands a t 3.00 (m), 3.36 (w), 3.42 (w), 6.90 (w), 7.09 (m), 7.19 (m), 7.35 (vs), 7.78 (m), 7.92 (m), 8.06 (m), 8.37 (s), 8.47 (vs), 8.83 (w), 8.97 (m), 9.12 (w), 9.36 (m), 9.55 (w), 10.36 (m), 10.55 (m), 11.12 (w), 11.90 (vs), 12.20 (s), and 13.28 (w) p . The addition reaction of methanol and 1- and 2-propanol to 1,2-dichlorotetrafluorocyclobutene was done under the same conditions mentioned above. The yields and physical properties of the 1 :1 adducts and the dehydrochlorinated 1:1 adducts are summarized in Tables I, 111, and IV. Addition Reactions of Alcohols to 1,2-Dichlorohexafluorocyc1opentene.-A mixture of 99 g. (1.65 moles) of 2-propanol and 114.4 g. (0.47 mole) of 1,2-dichlorohexafluorocyclopentene was sealed in a glass tube and irradiated a t room tem(6) All temperature readings are uncorrected. 1,2-Dichlorotetrafluorocyclobutene and 1,2-dichlorohexafluorocyclopentenewere obtained from the Peninsular Chem Research, Inc., and used without further purification. (7) A Hitachi-KGL-2 was employed using helium as the carrier gas at a flow rate of 54 cc./min. and a column temperature of 129O; a 2-m. column packed with 25% Silicone DC-550 was used.
MURAMATSU, INUKAI, AND UEDA
2548
VOL.30
TABLE I11 DICHLOROTETRAFLUOROCYCLOBUTYLC ARBINOLS
Fz,-fyf(oH: F2
c1 B.p., OC. (mm.)
R'
H H H CH3
101-102 106-107 104-105 98-100
(69) (50) (33) (51)
M - RCalod.
nmD
dzQ4
1.4180 1.4211 1.4233 1.4173
1.651 1.550 1.464 1.427
Found
34 67 39.29 43.91 43.91
%-
-Fluorine, Calod.
34.65 39.44 44.39 44.97
33.5 31.5 29.8 29.8
%-
Found
-Chlorine, Calod.
Found
33.2 31.3 30.0 31.9
31.2 29.4 27.8 27.8
31.0 29.1 25.9 25.8
TABLE IV CHLOROTETRAFLUOROCYCLOBUTENYLCARBINOLS Fz :lRR' (OH) F2
R'
YC-c
B.p., OC. (mm.)
naD
d 204
M --R -D -Calod.
96-98 (69) 1.4023 1.555 H H 89-90(52) 1.4025 1.445 H 92-94(41) 1.4090 1.381 87-88 (52) 1.4070 1.381 CH3 of 1,2-dichlorotetrafluorocyclobutene,6.12 p.
29.34 33.95 38.57 38.57
%-
%-
Found
-Fluorine, Calcd.
Found
-Chlorine, Calcd.
Found
Pa
29.85 34.51 39.13 38.96
39.9 37.2 34.8 34.8
39.6 37.2 33.7 34.8
18.6 17.3 16.2 16.2
18.7 17.2 17.3 16.6
6.03 6.06 6.06 6.09
YC-C,
TABLE V
CHLOROHEXAFLUOROCYCLOPENTENY LCARBINOLS
R
a
R'
B.p., OC. (mm.)
n%
d%
H H 104105 (90) 1,3910 1.656 CH3 H 89-90 (45)b C2Hs H 102 (45) 1.3997 1.482 CH3 CH3 90 (45) 1.4001 1.494 M.p. ycWc of 1,2-dichlorohexafluorocyclopentene, 6.12 p.
-MRDCalcd.
Found
34.11
34.52
43.35 43.92 43.35 43.60 60.5-61.5'.
%-
-Fluorine, Calcd.
Found
47.4 44.8 42.4 42.4
47.1 44.4 42.2 42.9
--Chlorine, %Calcd. Found
14.7 13.9 13.2 13.2
14.6 13.9 13.5 13.1
YC-C,
Pa
6.03 6.07 6.075 6.14
TABLE VI TETRAFLUOROCYCLOBUTENYLCARBINOLS
R
R'
B.p., O C . (mm.)
n2OD
d 204
CH3 CzHs
H H
104-105 (100) 99-100 (50)
1.3873 1,3952
1.376 1.307
perature to a total dosage 3.1 X lo7 r. for a period of 545 hr. After the recovery of the unchanged alcohol (89 g.) and halocyclopentene (16 g.), distillation of the irradiation products gave 101.5 g. (0.38 mole, 81% yield) of (2-chlorohexafluoro-1-cyclopentenyl)dimethylcarbinol,b .p. 89-91" (45 mm.), and 2 g. of a tarry residue. The infrared spectrum of the dimethylhalocyclopentenylcarbinol showed a free OH absorption band a t 2.78 p (sh), a broad hydrogen-bonded OH band a t 2.92 p , and a sharp C=C absorption band a t 6.14 p . Using the same procedure, ethanol and 1-propanol added to 1,2-dichlorohexafluorocyclopentenein yields of 46 and 28Yo7,, respectively. I n the addition of methanol (76 g., 2.32 moles) to the dichlorohexafluorocyclopentene (146.5 g., 0.60 mole), 8 g. of a fraction of b.p. 100-105" (8 mm.) was obtained along with 41.2 g. (0.17 mole, 29% yield) of (2-chlorohexafluoro-lcyclopentenyl)carbinol, b.p. 103-106' (90 mm.). When the fraction was allowed to remain a t room temperature, white needle crystals precipitated which were filtered and recrystallized from benzene. The crystalline material melted at 103'
YMRDCalcd.
29.09 33.70
%-
YC-c,
Found
-Fluorine, Calcd.
Found
P
29.12 33.79
44.7 41.3
43.7 41 .O
6.135 6.14
and was slightly soluble in carbon tetrachloride and freely soluble in methanol. Its infrared spectrum showed OH absorption a t 3.06 p and no C=C absorption band. The structure of the crystals was tentatively assigned as 1,l-bis(hydroxymethyl) -2-chloro-3,3,4,4,5,5-hexafluorocyclopentane. Anal. Calcd. for C ~ H ~ J F B OC1, Z : 13.0; F, 41.8. Found: C1, 13.1; F , 42.4. The ohvsical orooerties of the dehvdrochlorinated 1:1 adducts. alkyl(2%oroh~xafiuorocyclopenten~l)carbinols, are listed in Table V. Dechlorination of Alkyl(l,2-dichlorotetrafluorocyclobutyl)carbino1s.-To 12 g. (0.18 g.-atom) of zinc dust in 50 ml. of ethanol was added dropwise 29 g. (0.12 mole) of methyl(l,2-dichlorotetrafluorocyclobuty1)carbinol(a mixture of cas and tram form) for 15 min. The reaction mixture was heated a t about looo for 4 hr. and filtered. Dilute hydrochloric acid was added to the filtrate and the organic layer was separated and dried. Distillation gave 16.3 g. (0.096 mole, 80% yield) of methy1(3,3,4,4tetrafluoro-1-cyclobutenyl)carbinol,b.p. 103-105' (100 mm.).
AUGUST1965
2549
6p-(2,6-DICHLOROBENZOYLOXY)-2,4-CHOLESTADIENE
The infrared spectrum of the carbinol showed a free OH band a t 2.79 p (sh), a broad hydrogen-bonded OH band a t 3.00 p , and C=C band a t 6.135 p. Using the same procedure, 16.7 g. (0.066 mole) of ethyl(l,2dichlorotetrafluorocyclobuty1)carbinol with 7 g. (0.11 g.-atom) of zinc dust gave 9.4 g. (0.051 mole, 78% yield) of ethyl (3,34,4-tetrafluoro-l-cyclobutenyl)carbinol,b.p. 98-100' (50 mm.). Dehydration of Methy1(3,3,4,4-tetrafluoro-l-cyclobutenyl)carbinol.-To 19 g. (0.13 mole) of phosphoric anhydride was
added dropwise 15 g. (0.09 mole) of the carbinol and the reaction mixture was heated a t 140' for 40 min. and distilled. Redistillation of the product gave 8.5 g. (0.056 mole, 63% yield) of 3,3,4,4-tetrafluoro-1-cyclobutenylethylene,b.p. 99-loo', n% 1.3820. d2O4 1.260 (lit.1 b.p. 98-99', n% 1.3742, d24a 1.2588). Anal. Calcd. for CcH4F4: F, 50.0. Pound: F , 49.7. The tetrafluorocyclobutenylethylene was polymerized easily upon standing in the air or by peroxide treatment to give a transparent polymer.
Synthesis of 6p-(2,6-Dichlorobenzoyloxy)-2,4-cholestadiene and Related Compounds'" KIRKD. MCMICHAEL'~ AND GERALD A. SELTER Department of Chemistry, Washington State University, Pullman, Washington 99163 Received January 6, 1966 The preparations of 2-cholestene-5a,6p-diol (3) and two 6p ester derivatives are described. Treatment of the latter compounds with base yields 5a,6a-epoxy-2-cholestene,which may be converted to 3, to 6p-chloro-2The latter ester, whose preparation cholsten-5a-01, and to 6~-(2,6-dichlorobenzoyloxy)-2-cholesten-5a-o1. by esterification of 3 with 2,6-dichlorobenzoyl chloride was unsuccessful, may be dehydrated to yield the title compound. Some aspects of the spectra of these compounds are discussed.
I n connection with investigations of the direct and solvolytic nucleophilic displacement reactions of some conjugated dienes bearing suitable leaving groups in an allylic position, we required a convenient synthesis of 6p- (2,6-dichlorobenzoyloxy) -2,4-cholestadiene (1). This compound seems to be an appropriate substrate for observing long-range allylic rearrangements in a stereochemically well-defined system. The success of Summers, et u1.,2anb Wallis and Becker,2cand Young, et u1.,2d in preparing 6p-substituted 4-cholestenes by dehydration of the corresponding 5a-cholestanols with thionyl chloride in pyridine prompted our investigation of the same reaction in the 2-cholestene series. The preparation and therapeutically interesting biological activities of Az steroids bearing appropriate substituents elsewhere in the molecule have been the subjects of recent report^.^ 2-Cholesten-5a-ol-6-one (2) has been described by Reich, Walker, and C ~ l l i n s ,and ~ appeared to be an appropriate entry to the desired system. We have repeated their preparation on a larger scale and have shown that material of adequate quality for our purposes may be obtained by crystallization rather than chromatography. Treatment of the ketone 2 with lithium aluminum hydride afforded 2-cholestene-5a,Gp-diol (3) (see Chart I) in excellent yield as a nicely crystalline solid. The assignment of the fl configuration to the 6-hydroxyl group thus introduced is analogous to an example reported by Wallis and Becker2c who prepared cholestane-5a,6P-diol by lithium aluminum hydride reduction of cholestan-5a-ol-6-one. While lithium alu(1) (a) This work was supported by funds administered by the Research
Committee, The Graduate School, Washington State University. (b) To whom communications should be addressed. (2) (a) A. J. Fudge, C. W. Shoppee, and G. H. R. Summers, J . Chem. Soc., 958 (1954); (b) D. N . Jones, J. R. Lewis, C. W. Shoppee, and G. H. R. Summers, ibid., 2876 (1955); ( c ) E. J. Becker and E. S. Wallis, J . Ow. Chem., 30, 353 (1955); (d) R. E. Ireland, T. 1. Wrigley, and W. G. Young, J . Am. Chem. Soc., 80, 4604 (1958). (3) For some recent examples and references to earlier work, see J. A . Edwards, P. G. Holton, J. C. Orr, E. Necoechea, A . de la Roz, E. Segovia, R. Urquiza, and A. Bowers, J . Med. Chem., 6 , 174 (1963). (4) H. Reich, F. E. Walker, and R . W. Collins, J . Ow. Chem., 16, 1753 (1951).
CHARTI
\ OCOR 5a, R = cc13 b,R = CsH5
/ 3
H6 c1
7
I
OCO (2,6-CsHaCli) 8
1
minum hydride reduction of 6-keto steroids gives predominantly the 6p-hydroxy steroid it is usually possible to isolate some of the 6a epimer.5 In the present case, as in that of the corresponding reduction of cholestan-5a-o1-6-0ne,~~the normal preference for attack on the less hindered side is probably reinforced (5) C. W. Shoppee and G. H. R. Summers, J . Chem. S o c . , 3361 (1952).
